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Diagnosis of Acute Myocardial Infarction
Myocardial infarction (MI) describes the process of myocardial cell death caused by ischemia or the imbalance between myocardial oxygen supply via the coronary arteries and demand. In the United States each year, an estimated 1.1 million people experience an acute MI or die from coronary heart disease. In 2016, it was estimated that approximately every 34 seconds one American would have a coronary event and about every 1 minute 24 seconds an individual would die from a coronary event. According to the most recent World Health Organization report in 2015, coronary heart disease remains the leading cause of death worldwide. Hence the early recognition and diagnosis of acute MI is vital for the institution of therapy to limit myocardial damage, preserve cardiac function, and reduce mortality.
Acute coronary syndrome (ACS) refers to the constellation of clinical signs and symptoms caused by worsening myocardial ischemia. In the absence of myocardial damage, assessed by measuring cardiac biomarker levels, patients can be classified as having unstable angina. When myocardial damage is present, patients with ACS can be grouped into two major categories of acute MI: (1) patients with new ST segment elevation on the electrocardiogram (ECG) that is diagnostic of acute ST segment elevation myocardial infarction (STEMI), and (2) patients with non–ST segment elevation myocardial infarction (NSTEMI) who have elevated cardiac biomarkers in an appropriate clinical setting, with or without ischemic ECG changes.
Clinical trials have established the benefit of early reperfusion therapy in patients with STEMI and an early invasive strategy in patients with high-risk NSTEMI; thus a rapid and accurate assessment of patients with suspected acute MI is essential for optimal management. This chapter describes the diagnostic modalities for the evaluation of patients with suspected acute MI.
History
There have been considerable advances in the detection of myocardial injury and necrosis in the last several decades; as a result, the definition of MI has evolved over time. Beginning in the 1950s, the World Health Organization used epidemiologic data to define acute MI as the presence of at least two of the following three criteria: (1) clinical symptoms suggestive of myocardial ischemia, (2) ECG abnormalities, or (3) elevation in serum markers indicative of myocardial necrosis. Subsequently, the development of more sensitive and specific biomarkers and precise imaging techniques to detect subtle myocardial necrosis has led to further refinement of the diagnosis of MI. In 1999, a consensus conference convened by the European Society of Cardiology and the American College of Cardiology Foundation published the first universal definition of MI. With ongoing advances in the diagnosis and management of MI, this definition was updated in 2007 by a Global Task Force assembled from the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation. Most recently, in 2012, the same groups assembled and published the third universal definition of MI with the goals of standardizing cardiac biomarker detection, the use of cardiac imaging in the evaluation of a patient with MI, and the classification of different types of MIs.
Definition of Myocardial Infarction
MI is defined as myocardial necrosis caused by prolonged myocardial ischemia. The diagnosis of acute MI requires the rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value exceeding the 99th percentile of a normal reference population (the upper reference limit) and at least one of the following: symptoms of ischemia, ECG changes indicative of active ischemia (new ST segment–T wave changes or new left bundle branch block [LBBB]) or infarction (new pathologic Q waves), identification of an intracoronary thrombus by angiography or autopsy, imaging evidence of a new regional wall motion abnormality, or new loss of viable myocardium. The type of acute MI can be classified further depending on the etiology of the infarct ( Table 9.1 ). Prior MI is defined as pathologic Q waves, regardless of symptoms, in the absence of nonischemic causes, pathologic findings of a healed or healing MI, or imaging evidence of a region of nonviable myocardium.
TABLE 9.1
Universal Classification of Myocardial Infarction (MI)
Modified and adapted from Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol . 2012;60:1581–1598.
| Type | Description |
|---|---|
| 1 | Spontaneous MI resulting from an atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus |
| 2 | MI associated with ischemia due to an imbalance in myocardial oxygen supply and demand, such as in coronary endothelial dysfunction, coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension, or hypotension |
| 3 | MI resulting in cardiac death, with symptoms suggestive of myocardial ischemia, accompanied by new ischemic electrocardiogram changes, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood |
| 4a | MI associated with percutaneous coronary intervention |
| 4b | MI associated with stent thrombosis as documented by angiography or autopsy |
| 5 | MI associated with coronary artery bypass graft surgery |
Biochemical Markers of Acute Myocardial Infarction
The ideal biochemical marker to detect an acute MI should be present in high concentration in the myocardium, absent in noncardiac tissue, released rapidly in a linear fashion after myocardial necrosis, and should remain present in the serum long enough to be easily detectable by an inexpensive and widely available assay. Table 9.2 summarizes serum cardiac markers. Cardiac biomarkers are an essential component of the criteria used to establish the diagnosis of acute MI. Cardiac troponins (I or T) have become the preferred biomarkers for the detection of myocardial necrosis; their use is a class I indication in the diagnosis of MI. The improved sensitivity and tissue specificity of cardiac troponins compared with creatine kinase MB (CK-MB) and other conventional cardiac biochemical markers of acute MI has been well established. Troponins are not only useful for diagnostic implications but they also impart prognostic information and can assist in the risk stratification of patients presenting with suspected ACS.
TABLE 9.2
Biochemical Markers of Myocardial Necrosis
Modified from Adams J, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury: is MB creatine kinase the choice for the 1990's? Circulation . 1993;88:750–763.
| Marker | Initial Appearance (h) | Mean Time to Peak | Return to Basal | Sampling Schedule |
|---|---|---|---|---|
| Myoglobin | 1–4 | 6–7 h | 12–24 h | Initially, then every 1–2 h |
| CK–MB (tissue isoform) | 2–6 | 18 h | 48–72 h | Initially, then every 3–6 h |
| Cardiac troponin I | 3–6 | 24 h | 7–10 days | Initially, then every 3–6 h |
| Cardiac troponin T | 3–6 | 12–48 h | 10–14 days | Initially, then every 3–6 h |
| CK | 3–12 | 24 h | 72–96 h | Initially, then every 8 h |
| Lactate dehydrogenase (LDH) | 10 | 48–72 h | 10–14 days | Once at least 24 h after chest pain |
CK-MB , MB isoenzyme of creatine kinase (CK).
In addition to the established biomarkers of myocardial necrosis, B-type natriuretic peptide (BNP) and C-reactive protein (CRP) are pathologically diverse biomarkers that could potentially enhance risk stratification in ACS. Additionally, several novel markers of myocardial ischemia and their usefulness during acute MI are currently being evaluated in clinical studies. However, to date, measurement of more than one specific biomarker of myocardial necrosis is unnecessary and not recommended for establishing the diagnosis of MI. Furthermore, certain biomarkers should no longer be used in the evaluation of acute MI because of poor specificity secondary to their wide tissue distribution, including aspartate aminotransferase, total lactate dehydrogenase, and lactate dehydrogenase isoenzymes.
Detectable increases in cardiac biomarkers are indicative of myocardial injury. However, cardiac biomarker elevations are not synonymous with acute MI. Many disease states, such as sepsis, congestive heart failure, pulmonary embolism, myocarditis, intracranial hemorrhage, stroke, and renal failure can be associated with an increase in cardiac biomarkers. These elevations arise from mechanisms other than thrombotic coronary artery occlusion and require treatment of the underlying cause rather than the administration of antithrombotic and antiplatelet agents. Acute MI should be diagnosed when cardiac biomarkers are abnormal and the clinical setting is consistent with myocardial ischemia.
Troponin
Cardiac troponins are regulatory proteins that control the calcium-mediated interaction of actin and myosin, which results in contraction and relaxation in striated muscle. The troponin complex comprises three subunits: troponin C, which binds calcium; troponin I, which inhibits actin-myosin interactions; and troponin T, which attaches the troponin complex by binding to tropomyosin and facilitates contraction. Troponin C is expressed by cells in cardiac and skeletal muscle; in contrast, the amino acid sequences of troponins I and T are unique to cardiac muscle. This difference has allowed for the development of rapid, quantitative assays to detect elevations of cardiac troponins in the serum. Troponin is the preferred biomarker for use in the diagnosis of acute MI because of superior tissue specificity and sensitivity for MI and its usefulness as a prognostic indicator.
Diagnosis.
Troponin is released early in the course of acute MI. An increased concentration of cardiac troponin is defined as exceeding the 99th percentile of a normal reference population. Troponin exceeding this limit on at least one occasion in the setting of clinical myocardial ischemia is indicative of an acute MI. Elevated troponin can be detected within 3 to 4 hours after the onset of myocardial injury. Serum levels can remain increased for 7 to 10 days for troponin I and 10 to 14 days for troponin T ( Fig. 9.1 ).
The initial release of troponin is from the cellular cytosol, whereas the persistent elevation is a result of the slower dispersion of troponin from degrading cardiac myofilaments. As a result of these kinetics, the sensitivity of troponin increases with time. At 60 minutes after the onset of acute MI, the sensitivity is approximately 90%, but maximal sensitivity of troponin (≈99%) is not achieved until 6 or more hours after the initiation of myocardial necrosis. Blood samples for the measurement of troponin levels are recommended to be drawn at presentation and 6 to 9 hours later to optimize the clinical sensitivity for ruling in acute MI and the specificity for ruling out acute MI.
The sensitivity and specificity of cardiac troponins is approximately 95% and 90%, respectively, with serial testing up to 12 hours after arrival at the hospital. As a result of its high tissue specificity, cardiac troponin is associated with fewer false-positive results in the setting of concomitant skeletal muscle injury compared with CK-MB. This inherent characteristic of troponin is useful in the assessment of myocardial injury in patients with chronic muscle diseases, perioperative MIs, and after electrical cardioversion or blunt cardiac trauma. It is important to note that although cardiac troponin is highly tissue specific, its elevation does not indicate the mechanism of myocardial injury; if elevated troponins are found in the absence of myocardial ischemia, an evaluation for alternative etiologies of myocardial injury should be pursued.
More recently, there has been the ongoing development of high-sensitivity cardiac troponin assays, which are able to detect very low concentrations of cardiac troponins due to changes in how the assays are performed. High-sensitivity troponins are often abnormal earlier than conventional troponins in patients with acute MI. Because of this characteristic, high-sensitivity troponins can be used to safely and accurately rule out patients with suspected ACS more quickly than when using conventional troponins. However, uncertainties about appropriate cut-off values for high-sensitivity troponins, difficulty in distinguishing between acute and chronic causes of high-sensitivity troponin elevations, and lack of clarity regarding the optimal duration of the rule-out period for acute MI have prevented the mainstream use of this assay in current practice.
Thus, with the use of conventional troponin assays that do not reliably permit the very early (initial 1 to 2 hours) detection of myocardial necrosis, the diagnosis of acute MI in patients presenting within 6 hours of symptom onset must be based on the clinical scenario, ECG findings, and adjunctive imaging techniques. In the case of STEMI, reperfusion therapy should not be delayed by waiting for biomarkers confirmatory of myocardial injury.
Elevated troponins are not only vital to the diagnosis of NSTEMI but also serve to direct treatment by identifying patients who would benefit from an early invasive management strategy. In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18 (TACTICS–TIMI 18) study, patients with any increase in troponin who underwent early angiography (within 4 to 48 hours) and revascularization (if appropriate) achieved an approximately 55% reduction in the odds of death or MI compared with patients undergoing conservative management.
Prognosis.
In addition to the diagnostic value of troponin, cardiac troponins yield prognostic information. Prognosis is related partly to the extent of the increase in troponin in patients with an ischemic mechanism for myocardial injury. Increased concentrations of troponin are associated with angiographic findings of greater lesion complexity, impaired blood flow in the culprit artery, and decreased coronary microvascular perfusion.
Cardiac troponin has also been proven to be a potent independent predictor of recurrent ischemic events and the risk of death among patients presenting with ACS. The Thrombolysis in Myocardial Ischemia Phase IIIB (TIMI IIIB) trial showed that in patients presenting with ACS, mortality was consistently higher among patients with elevated troponin I (>0.4 ng/mL) at the time of admission. Additionally, there were statistically significant increases in mortality with increasing levels of troponin I. Even after adjustment for baseline variables known to be significantly associated with an increased risk of cardiac events, elevated troponin I was independently associated with increased risk of mortality. Additionally, the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIa) trial found that elevated troponin T (>0.1 ng/mL) was significantly predictive of 30-day mortality in patients with acute myocardial ischemia even after adjusting for ECG changes and CK-MB level.
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